Typical Autosomal Dominant Polycystic Kidney Disease Research Articles

Baseline characteristics of the Korean genetic cohort of inherited cystic kidney disease.

Identifying genetic mutations in individuals with inherited cystic kidney disease is necessary for precise treatment. We aimed to elucidate the genetic characteristics of cystic kidney disease in the Korean population. We conducted a 3-year prospective, multicenter cohort study at eight hospitals from May 2019 to May 2022. Patients with more than three renal cysts were enrolled and classified into two categories, typical autosomal dominant polycystic kidney disease (ADPKD) and atypical PKD. We identified the clinical characteristics and performed a genetic analysis using a targeted gene panel. A total of 725 adult patients were included in the study, of which 560 (77.2%) were diagnosed with typical ADPKD and 165 (22.8%) had atypical PKD. Among the typical ADPKD cases, the Mayo imaging classification was as follows: 1A (55, 9.9%), 1B (149, 26.6%), 1C (198, 35.8%), 1D (90, 16.3%), and 1E (61, 11.0%). The atypical PKD cases were classified as bilateral cystic with bilateral atrophic (31, 37.3%), lopsided (27, 32.5%), unilateral (nine, 10.8%), segmental (eight, 9.6%), bilateral cystic with unilateral atrophic (seven, 8.4%), and asymmetric (one, 1.2%). Pathogenic variants were found in 64.3% of the patients using the ciliopathy-related targeted gene panel. The typical ADPKD group demonstrated a higher discovery rate (62.3%) than the atypical PKD group (41.8%). We present a nationwide genetic cohort's baseline clinical and genetic characteristics for Korean cystic kidney disease.

#5114 THE GENOTYPE DISTRIBUTION IN A SINGLE-CENTRE COHORT OF PATIENTS WITH POLYCYSTIC KIDNEY DISEASE

Abstract Background and Aims Polycystic kidney disease (PKD) is one of the most common causes of chronic kidney disease (CKD) and could lead to the end-stage kidney disease (ESKD) both in adulthood and in childhood. In the last few years many genes were discovered to be associated with PKD beyond the classical genes PKD1 and PKD2, that account for the majority of patients with ADPKD (Autosomal Dominant Polycystic Kidney Disease), and PKHD1 and DZIPIL that are responsible of ARPKD (Autosomal Recessive Polycystic Kidney Disease). The new genes are associated with different type of extra-renal involvement and with variable chance to develop CKD or ESKD. Thus, it is important for clinicians to define what mutation is involved in each patient to improve care in a context of precision medicine. We here describe a cohort of 65 consecutive patients followed at our PKD outpatient clinic who underwent the genetic analysis. Method We conducted a retrospective study of patients followed at our PKD outpatient clinic who underwent a genetic test for clinical reasons. We recorded why test was performed, with which modality and what was the result. If the analysis was positive we analyzed if only one or more genes were found mutated and if they belong to new genes described as being involved in PKD or if they are usually described in association with different diseases. Then, we collected demographic and clinical information (age, sex, renal function/presence of absence of ESKD) and the radiological description of kidneys in order to distinguish between typical and atypical PKDs. Results Among the 65 patients of our cohort 28 (43%) were males and 37 (57%) were females, the mean age was 56±18.6 years old; 20% had ESKD. They underwent genetic analysis for different reasons: 31 because of atypical PKD forms, 6 to define a suspected de novo mutation, 14 as a familiar screening and 14 for a better prognosis definition or when they approached the kidney transplant. The genetic analysis was conducted in two main ways: sequencing of PKD1 and PKD2 genes according to modern standards or exome sequencing. The first type of analysis was used for typical ADPKD forms whereas the second type was used when patients displayed an atypical presentation for both cysts distribution and kidney diameter (usually not enlarged kidneys with multiple bilateral cysts) and in two patients in which PKD1 and PKD2 sequencing was negative despite the PKD phenotype. We found that 25% of patients were negative, and the others are almost equally distributed between typical gene mutations and mutations in other genes (40% and 35% respectively) (Figure 1A). Of those with typical mutation, 81% was PKD1 positive and 19% PKD2 positive, a distribution that reflects that of literature (Figure 1B). Of those with other genes positivity: 52% had a DNAJB11 mutation, 17% a mutations in other PKD genes (ALG8, LRP5, PKHD1, COL4A1, IFT140), 32% had a mutation in genes usually associated with CAKUT (congenital anomalies of kidney and urinary tract) or with syndromic or extra-renal diseases (Figure 1C). 18 patients presented with multiple mutations, usually 2, in one case three and in another 4. Of them, the 22% had a double PKD1 mutation, while the others showed mutations in different genes associated with syndromic or extra-renal diseases (Figure 1D). Conclusion Our cohort revealed a wide variety of genetic mutations and also an almost equal distribution between typical genes and atypical/other genes. This could be the result of the small number of patients involved and of the monocentric design of the study (we have a cluster of patients with DNAJB11 belonging to the same small geographical area), but also of the larger inclusion of patients presenting with atypical PKDs. Unfortunately a 25% of patients remained genetically unresolved despite the use of exome sequencing.

Nutritional Status is Associated With Preserved Kidney Function in Patients With Autosomal Dominant Polycystic Kidney Disease

Malnutrition is a common complication in autosomal dominant polycystic kidney disease (ADPKD). We examined whether nutritional status is associated with the preservation of kidney function, using a cohort of typical ADPKD. We enrolled ambulatory ADPKD patients in 9 tertiary medical centers in Korea from May 2019 to December 2021. We excluded patients who were aged less than 18years, who had known end-stage kidney disease at the time of enrollment, who had a diagnosis of atypical ADPKD, and who were Tolvaptan users. The primary outcome was an estimated glomerular filtration rate (eGFR) decline >3mL/min/1.73m2, based on nutritional status assessed by subjective global assessment (SGA). We also evaluated an eGFR decline >1mL/min/1.73m2, an increase in urine protein-creatinine ratio (UPCR)>0, and an increase in UPCR >0.3 as secondary outcomes, based on SGA after the 1-year follow-up. A logistic regression (LR) model was used to calculate the odds ratio (OR) for the primary outcome. Because there were differences in several baseline variables, such as Mayo classification, serum hemoglobin, serum creatinine, and UPCR between SGA groups, we matched propensity scores. In total, 805 patients were prospectively enrolled. Among them, 236 patients who had 1-year follow-up data and typical imaging findings were analyzed to evaluate the effect of nutritional status on kidney function. SGA was used to assess the nutritional status. The mean age was 45.0±13.3years, and 49.6% of the patients were female. The mean eGFR was 81.9mL/min/1.73m2. Among the 236 patients, 91 (38.6%) experienced a 1-year eGFR decline >3mL/min/1.73m2. When a multivariable LR was applied, SGA 3-6 was identified as a significant factor related to a 1-year eGFR decline >3mL/min/1.73m2 (adjusted OR=1.22 [1.04-1.43]; P=.017). Despite matching propensity scores, the 1-year eGFR decline >3mL/min/1.73m2 was still higher in the SGA 3-6 group regardless of proteinuria. Good nutritional status is associated with better-preserved kidney function in non-obese typical ADPKD patients who do not take Tolvaptan.

Factors Associated With the Development and Severity of Polycystic Liver in Patients With Autosomal Dominant Polycystic Kidney Disease.

Factors related to the development and severity of polycystic liver disease (PLD) have not been well established. We aimed to evaluate the genetic and epidemiologic risk factors of PLD in patients with autosomal dominant polycystic kidney disease (ADPKD). Adult patients with inherited cystic kidney disease were enrolled from May 2019 to May 2021. Demographic, clinical, and laboratory data were collected at the initial study visit. The severity of PLD was graded based on the height-adjusted total liver volume: < 1,000 mL/m (Gr1), 1,000-1,800 mL/m (Gr2), and > 1,800 mL/m (Gr3). Targeted exome sequencing was done by a gene panel including 89 ciliopathy-related genes. We searched out the relative factors to the presence and the severity of PLD using logistic regression analysis. Of 602 patients with typical ADPKD, 461 (76.6%) patients had PLD. The patients with PLD showed female predominance and a higher frequency of other ADPKD-related complications. The genetic variants with truncating mutation of PKD1 (PKD1-protein-truncating [PT]) or PKD2 commonly affected the development and severity of PLD. An older age, female sex, and higher kidney volume with Mayo classification 1C-1E was significantly associated with the development of PLD, but not with the severity of PLD. On the other hand, higher body mass index, lower hemoglobin, and higher alkaline phosphatase (ALP) were the significant risk factors of severe PLD (≥ Gr2). Hepatic involvement in ADPKD could be related to kidney manifestations and genetic variants including PKD1-PT or PKD2. Monitoring hemoglobin and ALP and evaluating the genetic variants might help predict severe PLD. Clinical Research Information Service Identifier: KCT0005580.

Identification and Characterization of Novel Mutations in Chronic Kidney Disease (CKD) and Autosomal Dominant Polycystic Kidney Disease (ADPKD) in Saudi Subjects by Whole-Exome Sequencing.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a condition usually caused by a single gene mutation and manifested by both renal and extrarenal features, eventually leading to end-stage renal disease (ESRD) by the median age of 60 years worldwide. Approximately 89% of ADPKD patients had either PKD1 or PKD2 gene mutations. The majority (85%) of the mutations are in the PKD1 gene, especially in the context of family history. Objectives: This study investigated the genetic basis and the undiscovered genes that are involved in ADPKD development among the Saudi population. Materials and Methods: In this study, 11 patients with chronic kidney disease were enrolled. The diagnosis of ADPKD was based on history and diagnostic images: CT images include enlargement of renal outlines, renal echogenicity, and presence of multiple renal cysts with dilated collecting ducts, loss of corticomedullary differentiation, and changes in GFR and serum creatinine levels. Next-generation whole-exome sequencing was conducted using the Ion Torrent PGM platform. Results: Of the 11 Saudi patients diagnosed with chronic kidney disease (CKD) and ADPKD, the most common heterozygote nonsynonymous variant in the PKD1 gene was exon15: (c.4264G &gt; A). Two missense mutations were identified with a PKD1 (c.1758A &gt; C and c.9774T &gt; G), and one patient had a PKD2 mutation (c.1445T &gt; G). Three detected variants were novel, identified at PKD1 (c.1758A &gt; C), PKD2L2 (c.1364A &gt; T), and TSC2 (deletion of a'a at the 3'UTR, R1680C) genes. Other variants in PKD1L1 (c.3813_381 4delinsTG) and PKD1L2 (c.404C &gt; T) were also detected. The median age of end-stage renal disease for ADPK patients in Saudi Arabia was 30 years. Conclusion: This study reported a common variant in the PKD1 gene in Saudi patients with typical ADPKD. We also reported (to our knowledge) for the first time two novel missense variants in PKD1 and PKD2L2 genes and one indel mutation at the 3'UTR of the TSC2 gene. This study establishes that the reported mutations in the affected genes resulted in ADPKD development in the Saudi population by a median age of 30. Nevertheless, future protein-protein interaction studies to investigate the influence of these mutations on PKD1 and PKD2 functions are required. Furthermore, large-scale population-based studies to verify these findings are recommended.

More dissimilarities than affinities between DNAJB11-PKD and ADPKD.

ABSTRACTBackgroundPolycystic kidney diseases (PKD) are an important cause of chronic kidney disease (CKD). Autosomal dominant polycystic kidney disease (ADPKD) due to PKD1 or PKD2 mutations is the most common form, but other genes can be responsible for ADPKD and its phenocopies. Among them, a form of atypical ADPKD caused by DNAJB11 mutations (DNAJB11-PKD) has been recently described.MethodsWe retrospectively recruited a cohort of 27 patients from six different families sharing common ancestries and harboring the same DNAJB11 mutation (c.100C>T, p.Arg34*) and we compared it with a cohort of 42 typical ADPKD patients.ResultsDNAJB11-PKD patients show small/normal-sized kidneys, with significantly smaller cysts and a slower progression to end-stage kidney disease (ESKD) than ADPKD patients. In the DNAJB11-PKD cohort, the cystic phenotype could not be detected by ultrasound in about half of the patients, but all cases with available computed tomography/magnetic resonance scans displayed cysts. Clinically, DNAJB11-PKD patients displayed proteinuria (mostly albuminuria). Compared with ADPKD, DNAJB11-PKD patients were older and had a higher prevalence of type 2 diabetes mellitus (19% versus 0%; P = 0.007) and nephrolithiasis (62% versus 29%; P = 0.01), whereas the prevalence of cardiac valvular defects was lower (4% versus 51%; P < 0.001).ConclusionsOverall, clinical features of DNAJB11-PKD were more subtle compared with those of ADPKD. DNAJB11-PKD shows a unique renal and extrarenal phenotype, clinical presentation and natural history. Therefore our data support that this genetic disease is classified separately from ADPKD.

POS-428 PROTEIN-TRUNCATING PKD1 MUTATIONS YET MILD AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE IS UNDER-RECOGNIZED

Progression of autosomal dominant polycystic kidney disease (ADPKD) is highly variable between patients. On average, protein-truncating PKD1 mutations are associated with the most severe kidney disease among all mutation classes, yet within family disease variability is a recognized feature of ADPKD. The penetrance of protein-truncating PKD1 mutations cannot be adequately evaluated if only index probands with severe disease are tested. Here, we evaluated the patients with protein-truncating PKD1 mutations yet mild kidney disease from the extended Toronto Genetic Epidemiologic Study of Polycystic Kidney Disease. The extended Toronto Genetic Epidemiologic Study of Polycystic Kidney Disease cohort included probands with ADPKD (n=612) and their affected relatives (n=778) from a total of 612 unrelated families. 487 patients from 442 unrelated families had both PKD1 and PKD2 sequencing and typical ADPKD imaging patterns by magnetic resonance imaging or computed tomography. Mayo Clinic Imaging Classification based on age- and height-adjusted total kidney volume was used to assess their cystic disease severity. Among 174 study patients with protein-truncating PKD1 mutations, 32 (18%) from 27 families were found to have mild disease based on imaging results (i.e. Mayo Clinic Imaging Class 1A-1B), with their mutations spanning across the entire gene. 23 of 32 were over the age of 30 making incorrect risk stratification unlikely. In patients with Mayo Clinic Imaging Class 1A-1B, the slopes of log-transformed height-adjusted total kidney volume (βPKD1= 1.0% larger kidney per year vs. βPKD2= 1.3% larger per year, P=0.3) and eGFR (βPKD1= -1.29 ml/min/1.73m2 per year vs. βPKD2= -1.46 ml/min/1.73m2 per year, P=0.6) overlap regardless of whether they had protein-truncating PKD1 or PKD2 mutation. Comparing patients with Mayo Clinic Imaging Class 1A-1B by multivariable analyses, patients with PKD2 mutations had only marginally smaller kidney volumes (β = -7.7%; 95% CI: -13.9% to -0.01%; P=0.02) and their eGFR was not significantly different (β = 9.0 ml/min/1.73m2; 95% CI: -0.4 to 18.3 ml/min/1.73m2, P=0.06) compared to those with protein-truncating PKD1 mutations. Most of these mildly affected patients with protein-truncating PKD1 mutations reported a positive family history of ADPKD in preceding generations and displayed significant intra-familial disease variability. One patient had confirmed somatic mosaicism. Despite having the most severe mutation class, 18% of patients with protein-truncating PKD1 mutations had mild disease based on clinical and imaging assessment that was similar to patients with PKD2 mutations. The presence of a positive family history of ADPKD in most of these patients makes somatic mosaicism an unlikely explanation for their mild disease. By contrast, significant within-family variability suggests a protective modifier effect from yet unknown genetic and environmental factors.

Patients with Protein-Truncating PKD1 Mutations and Mild ADPKD.

Progression of autosomal dominant polycystic kidney disease (ADPKD) is highly variable. On average, protein-truncating PKD1 mutations are associated with the most severe kidney disease among all mutation classes. Here, we report that patients with protein-truncating PKD1 mutations may also have mild kidney disease, a finding not previously well recognized. From the extended Toronto Genetic Epidemiologic Study of Polycystic Kidney Disease, 487 patients had PKD1 and PKD2 sequencing and typical ADPKD imaging patterns by magnetic resonance imaging or computed tomography. Mayo Clinic Imaging Classification on the basis of age- and height-adjusted total kidney volume was used to assess their cystic disease severity; classes 1A or 1B were used as a proxy to define mild disease. Multivariable linear regression was performed to test the effects of age, sex, and mutation classes on log-transformed height-adjusted total kidney volume and eGFR. Among 174 study patients with typical imaging patterns and protein-truncating PKD1 mutations, 32 (18%) were found to have mild disease on the basis of imaging results (i.e., Mayo Clinic Imaging class 1A-1B), with their mutations spanning the entire gene. By multivariable analyses of age, sex, and mutation class, they displayed mild disease similar to patients with PKD2 mutations and Mayo Clinic Imaging class 1A-1B. Most of these mildly affected patients with protein-truncating PKD1 mutations reported a positive family history of ADPKD in preceding generations and displayed significant intrafamilial disease variability. Despite having the most severe mutation class, 18% of patients with protein-truncating PKD1 mutations had mild disease on the basis of clinical and imaging assessment. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_18_CJN11100720_final.mp3.

Genomic diagnostics in polycystic kidney disease: an assessment of real-world use of whole-genome sequencing.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is common, with a prevalence of 1/1000 and predominantly caused by disease-causing variants in PKD1 or PKD2. Clinical diagnosis is usually by age-dependent imaging criteria, which is challenging in patients with atypical clinical features, without family history, or younger age. However, there is increasing need for definitive diagnosis of ADPKD with new treatments available. Sequencing is complicated by six pseudogenes that share 97% homology to PKD1 and by recently identified phenocopy genes. Whole-genome sequencing can definitively diagnose ADPKD, but requires validation for clinical use. We initially performed a validation study, in which 42 ADPKD patients underwent sequencing of PKD1 and PKD2 by both whole-genome and Sanger sequencing, using a blinded, cross-over method. Whole-genome sequencing identified all PKD1 and PKD2 germline pathogenic variants in the validation study (sensitivity and specificity 100%). Two mosaic variants outside pipeline thresholds were not detected. We then examined the first 144 samples referred to a clinically-accredited diagnostic laboratory for clinical whole-genome sequencing, with targeted-analysis to a polycystic kidney disease gene-panel. In this unselected, diagnostic cohort (71 males :73 females), the diagnostic rate was 70%, including a diagnostic rate of 81% in patients with typical ADPKD (98% with PKD1/PKD2 variants) and 60% in those with atypical features (56% PKD1/PKD2; 44% PKHD1/HNF1B/GANAB/ DNAJB11/PRKCSH/TSC2). Most patients with atypical disease did not have clinical features that predicted likelihood of a genetic diagnosis. These results suggest clinicians should consider diagnostic genomics as part of their assessment in polycystic kidney disease, particularly in atypical disease.

Detection and characterization of mosaicism in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited, progressive nephropathy accounting for 4-10% of end stage renal disease worldwide. PKD1 and PKD2 are the most common disease loci, but even accounting for other genetic causes, about 7% of families remain unresolved. Typically, these unsolved cases have relatively mild kidney disease and often have a negative family history. Mosaicism, due to de novo mutation in the early embryo, has rarely been identified by conventional genetic analysis of ADPKD families. Here we screened for mosaicism by employing two next generation sequencing screens, specific analysis of PKD1 and PKD2 employing long-range polymerase chain reaction, or targeted capture of cystogenes. We characterized mosaicism in 20 ADPKD families; the pathogenic variant was transmitted to the next generation in five families and sporadic in 15. The mosaic pathogenic variant was newly discovered by next generation sequencing in 13 families, and these methods precisely quantified the level of mosaicism in all. All of the mosaic cases had PKD1 mutations, 14 were deletions or insertions, and 16 occurred in females. Analysis of kidney size and function showed the mosaic cases had milder disease than a control PKD1 population, but only a few had clearly asymmetric disease. Thus, in a typical ADPKD population, readily detectable mosaicism by next generation sequencing accounts for about 1% of cases, and about 10% of genetically unresolved cases with an uncertain family history. Hence, identification of mosaicism is important to fully characterize ADPKD populations and provides informed prognostic information.

Identifying gene mutations of Chinese patients with polycystic kidney disease through targeted next-generation sequencing technology.

BackgroundPolycystic kidney disease (PKD) is the most common hereditary kidney disease. The main mutational genes causing autosomal dominant polycystic kidney disease (ADPKD) are PKD1 and PKD2 as well as some rare pathogenic genes. Unilateral PKD is rare in clinics, and its association with gene mutations is unclear.MethodsTargeted next‐generation sequencing (NGS) was performed to detect the renal ciliopathy‐associated genes (targeted NGS panel including 63 genes) in PKD patients.ResultsForty‐eight PKD1 and PKD2 mutation sites were detected in 44 bilateral PKD patients, of which 48 were PKD1 mutation sites (87.5%) and six were PKD2 mutation sites (12.5%). All of which exhibited typical ADPKD. Furthermore, we detected HNF1B heterozygous mutations in three families. Although these three patients showed HNF1B heterozygous mutations, their clinical characteristics differed and showed phenotypic heterogeneity.ConclusionsTargeted NGS panel was helpful in detecting typical ADPKD patients and even in non‐typical PKD patients. Macromutation in HNF1B may lead to bilateral PKD. The 16 novel PKD gene mutation sites and two novel PKD2 gene mutation sites discovered in this study have some significance in genetic counseling for ADPKD patients, and increase the number of studied families and expand the mutation database of ADPKD.

Exome sequencing of Saudi Arabian patients with ADPKD

Purpose: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive development of kidney cysts and enlargement and dysfunction of the kidneys. The Consortium of Radiologic Imaging Studies of the Polycystic Kidney Disease (CRISP) cohort revealed that 89.1% had either a PKD1 or PKD2 mutation. Of the CRISP patients with a genetic cause detected, mutations in PKD1 accounted for 85%, while mutations in the PKD2 accounted for the remaining 15%. Here, we report exome sequencing of 16 Saudi patients diagnosed with ADPKD and 16 ethnically matched controls.Methods: Exome sequencing was performed using combinatorial probe-anchor synthesis and improved DNA Nanoballs technology on BGISEQ-500 sequencers (BGI, China) using the BGI Exome V4 (59 Mb) Kit. Identified variants were validated with Sanger sequencing.Results: With the exception of GC-rich exon 1, we obtained excellent coverage of PKD1 (mean read depth = 88) including both duplicated and non-duplicated regions. Of nine patients with typical ADPKD presentations (bilateral symmetrical kidney involvement, positive family history, concordant imaging, and kidney function), four had protein truncating PKD1 mutations, one had a PKD1 missense mutation, and one had a PKD2 mutation. These variants have not been previously observed in the Saudi population. In seven clinically diagnosed ADPKD cases but with atypical features, no PKD1 or PKD2 mutations were identified, but rare predicted pathogenic heterozygous variants were found in cystogenic candidate genes including PKHD1, PKD1L3, EGF, CFTR, and TSC2.Conclusions: Mutations in PKD1 and PKD2 are the most common cause of ADPKD in Saudi patients with typical ADPKD. Abbreviations: ADPKD: Autosomal dominant polycystic kidney disease; CFTR: Cystic fibrosis transmembrane conductance regulator; EGF: Epidermal growth factor; MCIC: Mayo Clinic Imaging Classification; PKD: Polycystic kidney disease; TSC2: Tuberous sclerosis complex 2

Temporal and geographical external validation study and extension of the Mayo Clinic prediction model to predict eGFR in the younger population of Swiss ADPKD patients

BackgroundPrediction models in autosomal dominant polycystic kidney disease (ADPKD) are useful in clinical settings to identify patients with greater risk of a rapid disease progression in whom a treatment may have more benefits than harms. Mayo Clinic investigators developed a risk prediction tool for ADPKD patients using a single kidney value. Our aim was to perform an independent geographical and temporal external validation as well as evaluate the potential for improving the predictive performance by including additional information on total kidney volume.MethodsWe used data from the on-going Swiss ADPKD study from 2006 to 2016. The main analysis included a sample size of 214 patients with Typical ADPKD (Class 1). We evaluated the Mayo Clinic model performance calibration and discrimination in our external sample and assessed whether predictive performance could be improved through the addition of subsequent kidney volume measurements beyond the baseline assessment.ResultsThe calibration of both versions of the Mayo Clinic prediction model using continuous Height adjusted total kidney volume (HtTKV) and using risk subclasses was good, with R2 of 78% and 70%, respectively. Accuracy was also good with 91.5% and 88.7% of the predicted within 30% of the observed, respectively. Additional information regarding kidney volume did not substantially improve the model performance.ConclusionThe Mayo Clinic prediction models are generalizable to other clinical settings and provide an accurate tool based on available predictors to identify patients at high risk for rapid disease progression.

Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations to PKD1 or PKD2, triggering progressive cystogenesis and typically leading to end-stage renal disease in midlife. The phenotypic spectrum, however, ranges from in utero onset to adequate renal function at old age. Recent patient data suggest that the disease is dosage dependent, where incompletely penetrant alleles influence disease severity. Here, we have developed a knockin mouse model matching a likely disease variant, PKD1 p.R3277C (RC), and have proved that its functionally hypomorphic nature modifies the ADPKD phenotype. While Pkd1+/null mice are normal, Pkd1RC/null mice have rapidly progressive disease, and Pkd1RC/RC animals develop gradual cystogenesis. These models effectively mimic the pathophysiological features of in utero-onset and typical ADPKD, respectively, correlating the level of functional Pkd1 product with disease severity, highlighting the dosage dependence of cystogenesis. Additionally, molecular analyses identified p.R3277C as a temperature-sensitive folding/trafficking mutant, and length defects in collecting duct primary cilia, the organelle central to PKD pathogenesis, were clearly detected for the first time to our knowledge in PKD1. Altogether, this study highlights the role that in trans variants at the disease locus can play in phenotypic modification of dominant diseases and provides a truly orthologous PKD1 model, optimal for therapeutic testing.

Identification of Gene Mutations in Autosomal Dominant Polycystic Kidney Disease through Targeted Resequencing

Mutations in two large multi-exon genes, PKD1 and PKD2, cause autosomal dominant polycystic kidney disease (ADPKD). The duplication of PKD1 exons 1-32 as six pseudogenes on chromosome 16, the high level of allelic heterogeneity, and the cost of Sanger sequencing complicate mutation analysis, which can aid diagnostics of ADPKD. We developed and validated a strategy to analyze both the PKD1 and PKD2 genes using next-generation sequencing by pooling long-range PCR amplicons and multiplexing bar-coded libraries. We used this approach to characterize a cohort of 230 patients with ADPKD. This process detected definitely and likely pathogenic variants in 115 (63%) of 183 patients with typical ADPKD. In addition, we identified atypical mutations, a gene conversion, and one missed mutation resulting from allele dropout, and we characterized the pattern of deep intronic variation for both genes. In summary, this strategy involving next-generation sequencing is a model for future genetic characterization of large ADPKD populations.

Incompletely Penetrant PKD1 Alleles Mimic the Renal Manifestations of ARPKD

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutation in PKD1 or PKD2, is usually an adult-onset disorder but can rarely manifest as a neonatal disease within a family characterized by otherwise typical ADPKD. Coinheritance of a hypomorphic PKD1 allele in trans with an inactivating PKD1 allele is one mechanism that can cause early onset ADPKD. Here, we describe two pedigrees without a history of cystic kidney disease that each contain two patients with onset of massive PKD in utero. The presentations were typical of autosomal recessive PKD (ARPKD) but they were not linked to the known ARPKD gene, PKHD1. Mutation analysis of the ADPKD genes provided strong evidence that both families inherited, in trans, two incompletely penetrant PKD1 alleles. These patients illustrate that PKD1 mutations can manifest as a phenocopy of ARPKD with respect to renal involvement and highlight the perils of linkage-based diagnostics in ARPKD without positive PKHD1 mutation data. Furthermore, the phenotypic overlap between ARPKD and these patients resulting from incomplete penetrant PKD1 alleles support a common pathogenesis for these diseases.

Inheritance of a Stable Mutation in a Family with Early-Onset Disease

Autosomal/dominant polycystic kidney disease (ADPKD) exhibits a high inter- and intrafamilial heterogeneity partly explained by the involvement of at least 3 different genes in the disorder transmission. PKD1, the major locus, is located on chromosome 16p. The occurrence of very early-onset cases of ADPKD (sometimes in utero) in a few PKD1 families or the increased severity of the disease in successive generations raise the question of anticipation. This is a subject of controversial discussion. This report deals with the molecular analysis in families with very early-onset ADPKD. The finding of the same stable mutation with such different phenotypes rules out a dynamic mutation. The molecular basis of severe childhood PKD in typical ADPKD families remains unclear; it may include segregation of modifying genes or unidentified factors and the two-hit mechanism.